Stimulators of soluble guanylate cyclase (sGC) inhibit experimental skin fibrosis of different aetiologies
Stimulators of soluble guanylate cyclase (sGC) inhibit experimental skin fibrosis of different aetiologies
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DOI：
10.1136/annrheumdis-2014-206809
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发表时间：
2015-08-01
影响因子：
27.4
通讯作者：
Distler, Joerg H. W.
中科院分区：
文献类型：
--
作者：
Dees, Clara;Beyer, Christian;Distler, Joerg H. W.
目的可溶性鸟苷酸环化酶（sGC）的刺激剂最近被证明可以抑制转化生长因子β信号转导。在这里，我们的目的是证明利奥西呱，用于系统性硬化症（SSc）临床试验的候选药物，在实验性纤维化中是有效的，并将其疗效与磷酸二酯酶V抑制剂进行比较，磷酸二酯酶V抑制剂也会增加细胞内环磷酸鸟苷的水平。在博来霉素诱导的纤维化和硬皮病慢性移植物抗宿主病（cGvHD）模型中。利奥西呱的剂量为0.1-3 mg/kg，每日两次，西地那非的剂量为3-10 mg/kg，每日两次。利奥西呱还改善了cGvHD模型中的胃肠道纤维化。抗纤维化作用与细胞外信号调节激酶磷酸化水平降低有关。3和10 mg/kg剂量的西地那非产生轻度抗纤维化作用，与1和3 mg/kg riociguat.Conclusions相比，这些数据显示riociguat对实验性皮肤和器官纤维化具有强效抗纤维化作用。这些发现表明利奥西呱在治疗纤维化疾病，尤其是SSc方面的作用。目前正在SSc患者中开展一项利奥西呱的II期研究。
Objectives Stimulators of the soluble guanylate cyclase (sGC) have recently been shown to inhibit transforming growth factor-beta signalling. Here, we aimed to demonstrate that riociguat, the drug candidate for clinical trials in systemic sclerosis (SSc), is effective in experimental fibrosis and to compare its efficacy to that of phosphodiesterase V inhibitors that also increase the intracellular levels of cyclic guanosine monophosphate.Methods The antifibrotic effects of riociguat and sildenafil were compared in the tight-skin 1 model, in bleomycin-induced fibrosis and in a model of sclerodermatous chronic graft-versus-host-disease (cGvHD). Doses of 0.1-3 mg/kg twice a day for riociguat and of 3-10 mg/kg twice a day for sildenafil were used.Result Riociguat dose-dependently reduced skin thickening, myofibroblast differentiation and accumulation of collagen with potent antifibrotic effects at 1 and 3 mg/kg. Riociguat also ameliorated fibrosis of the gastrointestinal tract in the cGvHD model. The antifibrotic effects were associated with reduced phosphorylation of extracellular signal-regulated kinases. Sildenafil at doses of 3 and 10 mg/kg exerted mild antifibrotic effects that were significantly less pronounced compared with 1 and 3 mg/kg riociguat.Conclusions These data demonstrated potent antifibrotic effects of riociguat on experimental skin and organ fibrosis. These findings suggest a role for riociguat for the treatment of fibrotic diseases, especially for the treatment of SSc. A phase II study with riociguat in patients with SSc is currently starting.